, Volume 85, Issue 3, pp 309–314 | Cite as

Behavioral effects of a novel kappa opioid analgesic, U-50488, in rats and rhesus monkeys

  • A. H. Tang
  • R. J. Collins
Original Investigations


U-50488 [trans-3,4-dichloro-N-(2-(1-pyrrolidinyl)cyclohexyl)-benzeneacetamide] is a structurally novel analgesic reported to have specific kappa opioid receptor agonist properties. Potent antinociceptive activity was demonstrated in rhesus monkeys and the effect was reversed by naloxone. The overt behavioral effects of U-50488 at supra-analgesic doses more closely resembled those of ethylketocyclazocine (EKC) than morphine. In monkeys trained to discriminate a 10-μg/kg dose of EKC from saline, the stimulus effects generalized completely to U-50488 and other kappa agonists (e.g., bremazocine, cyclazocine), but not to the pure mu agonists. Like the other kappa agonists, U-50488 produced diuresis in monkeys by a naloxone-sensitive mechanism. In drug-naive rats offered continuous opportunity to self-administer drugs IV, most rats self-administered morphine or EKC, but none of the rats self-administered U-50488 at a rate above that of a group offered saline. Rats with continuous IV infusion of U-50488 for 3 weeks exhibited few abstinence signs and no weight loss when challenged with an injection of naloxone or after abrupt cessation of drug infusion. These experimental results support the previous reports in mice that U-50488 is a very selective kappa opioid agonist in rats and rhesus monkeys.

Key words

Kappa opioid agonist Rhesus monkeys Analgesia Diuresis Behavioral effects Drug dependence Self-administration 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Aceto MD, Harris LS, Dewey WL, May EL (1979) Annual report: Dependence studies of new compounds in the rhesus monkeys. Research Monograph Series #27, The Committee on Problems of Drug Dependence, Inc., p 337Google Scholar
  2. Brady KT, Balster RL (1982) Discriminative stimulus properties of stereoisomers of cyclazocine in phencyclidine-trained squirrel monkeys. Life Sci 31:541–549Google Scholar
  3. Collins RJ, Weeks JR, Cooper MM, Good PI, Russell RR (1984) Prediction of abuse liability of drugs using i.v. self-administration by rats. Psychopharmacology 82:6–13Google Scholar
  4. Hein DW, Young AM, Herling S, Woods JH (1981) Pharmacological analysis of the discriminative stimulus characteristics of ethylketocyclazocine in the rhesus monkey. J Pharmacol Exp Ther 218:7–15Google Scholar
  5. Herling S, Shannon HG (1982) Discriminative effects of ethylketocyclazocine in the rat: stereospecificity and antagonism by naloxone. Life Sci 31:2371–2374Google Scholar
  6. Lahti RA, Von Voigtlander PF, Barsuhn C (1982) Properties of a selective kappa agonist, U-50488H. Life Sci 31:2257–2260Google Scholar
  7. Leander JD (1983) A kappa opioid effect: Increased urination in the rat. J Pharmacol Exp Ther 224:89–94Google Scholar
  8. Martin WR, Eades CG, Thompson JA, Huppler RG, Gilbert PE (1976) The effects of morphine-and nalorphine-like drugs in the nondependent and morphine-dependent chronic spinal dog. J Pharmacol Exp Ther 197:517–532Google Scholar
  9. Maurer R (1982) Multiplicity of opiate receptors in different species. Neurosci Lett 30:303–307Google Scholar
  10. Pasternak GW (1980) Multiple opiate receptors: (3H)-ethylketocyclazocine receptor binding and ketocyclazocine analgesia. Proc Natl Acad Sci USA 77:3691–3694Google Scholar
  11. Romer D, Buscher H, Hill RC, Maurer R, Petcher TJ, Welle HBA, Bakel HCCK, Akkerman AM (1980) Bremazocine: A potent, long-acting opiate kappa agonist. Life Sci 27:971–978Google Scholar
  12. Romer D, Buscher HH, Hill RC, Maurer R, Petcher TJ, Zengner H, Benzon W, Finner E, Milkowski W, Thies PW (1982) An opioid benzodiazepine. Nature 298:759–760Google Scholar
  13. Tang AH, Code RA (1983) Discriminative stimulus properties of nalorphine in the rhesus monkeys. J Pharmacol Exp Ther 227:563–569Google Scholar
  14. Teiger DG (1974) Induction of physical dependence on morphine codeine and meperidine in the rat by continuous infusion. J Pharmacol Exp Ther 190:480–415Google Scholar
  15. Von Voigtlander PF, Lahti RA, Ludens JH (1983) U-50488: A selective and structurally novel non-mu (kappa) opioid agonist. J Pharmacol Exp Ther 224:7–12Google Scholar
  16. Von Voigtlander PF, Lewis RA (1982) U-50488. A selective kappa opioid agonist: comparsion to other reputed kappa agonists. Prog Neuropsychopharmacol Biol Psychiatr 6:467–470Google Scholar
  17. Ward SJ, Takemori AE (1983) Relative involvement of mu, kappa and delta receptor mechanisms in opiate-mediated antinociception in mice. J Pharmacol Exp Ther 224:525–530Google Scholar
  18. Weeks JR (1962) Experimental morphine addiction: Method for automatic intravenous injections in unrestrained rats. Science 138:143–144Google Scholar
  19. Weeks JR (1972) Long-term intravenous infusion. In: Meyers RO (ed) Methods in psychobiology, Vol. 2, London: Academic Press, pp 155–168Google Scholar
  20. Weeks JR, Collins RJ (1979) Dose and physical dependence as factors in the self-administration of morphine by rats. Psychopharmacology 65:171–177Google Scholar
  21. Woods JH, Fly CL, Swain HH (1978) Behavioral actions of some N-furyl benzomor-phans and ketazocine in rhesus monkeys and mice. In: Van Ree, Terenius (eds) Characteristics and functions of opioids. Biomedical Press, pp 403–411Google Scholar
  22. Woods JH, Smith CB, Medzibradsky F, Swain HH (1979) Preclinical testing of new analgesic drugs. In: Beers RF Jr, Bassett EG (eds) Mechanisms of pain and analgesic compounds. Raven Press, pp 429–445Google Scholar

Copyright information

© Springer-Verlag 1985

Authors and Affiliations

  • A. H. Tang
    • 1
  • R. J. Collins
    • 1
  1. 1.CNS ResearchThe Upjohn CompanyKalamazooUSA

Personalised recommendations